Griseofulvin derivatives

ABSTRACT

The present invention relates to compounds of the following general formula (I), or to a pharmaceutically acceptable salt thereof, as well as to the uses thereof as a drug, in particular for treating cancerous or precancerous hyperproliferative conditions, and to the pharmaceutical compositions containing same.

This application is a Divisional of copending application Ser. No.14/418,728, filed on Jan. 30, 2015, which was filed as PCT InternationalApplication No. PCT/EP2013/066169 on Aug. 1, 2013, which claims thebenefit under 35 U.S.C. §119(a) to patent application Ser. No. 1257482,filed in FRANCE on Aug. 1, 2012, all of which are hereby expresslyincorporated by reference into the present application.

The present invention relates to derivatives of griseofulvin and to theuse thereof for the treatment of cancerous and precanceroushyperproliferative pathologies.

Griseofulvin 1 is a natural molecule isolated from cultures offilamentous fungi Penicilium griseofulvum [J. Chem. Soc. 1958, 360-365].It is used in the treatment of fungal skin disorders in human and isalso used in veterinary medicine. It is chiefly given via oral route atdoses of 0.5 to 1.0 gram per day in human.

While the mechanism of action of griseofulvin on fungi still remains illunderstood, several studies indicate possible involvement inperturbation of the microtubular network [FEBS Letters 1978, 259-263;PNAS 2005, 978-9883; Cancer Res., 2007, 6342-6350] in eukaryote cells toexplain its low cytotoxicity and anti-cancer potential.

With a view to improving the anti-tumour properties of griseofulvin,derivatives of griseofulvin substituted at 2′ with oxygen- orsulfur-containing groups [J. Med. Chem. 2009, 3342-3347] have beensynthesised. However none of these products has displayed sufficientpotential for use as drug to treat cancerous and pre-canceroushyperproliferative pathologies.

The inventors have surprisingly discovered that the adding of particulargroups at 2′ and/or 3′ allows the obtaining of cytotoxic derivativesthat are more powerful than griseofulvin and its previously describedanalogues, and having remarkable activity on cancer lines particularlyresistant to known cytotoxics.

The subject of the present invention is therefore a compound offollowing general formula (I):

-   or a pharmaceutically acceptable salt thereof,-   where:    -   represents a single or double bond;    -   Y is C═O, C═S, CH₂, CH—OR₁, CHN₃, CHNR₂R₃, C═N—OR₄, C═N—NR₅R₆,        advantageously a C═O or CH—OR₁ group; and    -   either Z is a —S(O)R₇ or —S(O)₂R₇ group and X is a CH—R₈ group        when        represents a single bond or C—R₈ when        represents a double bond;    -   or Z is a hydrogen atom or a R₉ group, and X is a CH—R₁₀ group        when        represents a single bond or C—R₁₀ when        represents a double bond,-   with:

R₁ to R₅ each independently representing a hydrogen atom or a(C₁-C₆)alkyl, aryl, (C₁-C₆)alkyl-aryl, aryl-(C₁-C₆)alkyl or 5- or6-membered heterocycle group;

R₆ representing a hydrogen atom or a (C₁-C₆)alkyl, aryl,(C₁-C₆)alkyl-aryl, aryl-(C₁-C₆)alkyl, C(O)NH₂, C(S)NH₂ or 5- or6-membered heterocycle group;

R₇ representing a (C₁-C₆)alkyl, aryl, (C₁-C₆)alkyl-aryl,aryl-(C₁-C₆)alkyl or 5- or 6-membered heterocycle group;

R₈ representing —R₁₁, —NHR₁₁, —CH₂—NHR₁₁, —CH₂—NH—C(O)—R₁₁, —NH—CH₂—R₁₁,—NH—NH—R₁₁, —NH—C(O)—R₁₁, —NH—C(O)—CH₂—R₁₁, —NH—CH₂—C(O)—R₁₁,—NH—CH₂—C(O)—O—R₁₁, —NH—CH₂—C(O)—NH—R₁₁, —NH—SO₂—R₁₁, —S(O)—R₁₁,—SO₂—R₁₁, —S(O)—CH₂—R₁₁, —SO₂—CH₂—R₁₁ or —NR₁₂R₁₃;

R₉ representing —R₁₄, —NHR₁₄, —CH₂—NHR₁₄, —CH₂—NH—C(O)—R₁₄, —NH—CH₂—R₁₄,—NH—NH—R₁₄, —NH—C(O)—R₁₄, —NH—C(O)—CH₂—R₁₄, —NH—CH₂—C(O)—R₁₄,—NH—CH₂—C(O)—O—R₁₄, —NH—CH₂—C(O)—NH—R₁₄, —NH—SO₂—R₁₄, —S(O)—R₁₄,—SO₂—R₁₄, —S(O)—CH₂—R₁₄, —SO₂—CH₂—R₁₄ or —NR₁₆R₁₇;

R₁₀ representing a —S(O)R₁₅ or —S(O)₂R₁₅ group;

R₁₁ representing a hydrogen atom or a (C₁-C₆)alkyl, carbocycle,heterocycle, biaryl, carbocycle-(C₁-C₆)alkyl or heterocycle-(C₁-C₆)alkylgroup, optionally substituted;

R₁₂ and R₁₃ together forming, with their carrier nitrogen atom, aheterocycle optionally substituted with a —R₁₁, —OR₁₁ or —NHR₁₁ group;

R₁₄ representing a (C₁-C₆)alkyl, carbocycle, heterocycle, biaryl,carbocycle-(C₁-C₆)alkyl or heterocycle-(C₁-C₆)alkyl group, optionallysubstituted;

R₁₅ representing optionally substituted (C₁-C₆)alkyl group, optionallysubstituted aryl group, (C₁-C₆)alkyl-aryl, aryl-(C₁-C₆)alkyl,carbocycle, optionally substituted heterocycle, biaryl,carbocycle-(C₁-C₆)alkyl or heterocycle-(C₁-C₆)alkyl; and

R₁₆ and R₁₇ together forming, with their carrier nitrogen atom, aheterocycle optionally substituted with a —R₁₄, —OR₁₄ or —NHR₁₄ group.

The absolute stereochemistry at the spiro ring junction and alpha carboncarrying a methyl group is such as indicated in formula (I) above. Inaddition, the

portion of the molecule of above-mentioned formula (I) may comprise oneor more other asymmetric carbons which may each be present in the R or Sconfiguration or else in the form of a mixture of the two configurationsR and S in any proportion, in particular in equimolar proportions.

In the present invention by “pharmaceutically acceptable” is meant thatwhich can be used to prepare a pharmaceutical composition which isgenerally safe, non-toxic and neither biologically nor otherwiseadverse, and which is acceptable for veterinary use as well as for humanpharmaceutical use.

By “pharmaceutically acceptable salts” of a compound in this inventionit is meant to designate salts that are pharmaceutically acceptable asdefined above and which have the desired pharmacological activity of theparent compound.

In particular these are acid addition salts formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like; or formed with organic acids such asacetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid,citric acid, ethane-sulfonic acid, fumaric acid, glucoheptonic acid,gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonicacid, propionic acid, salicylic acid, succinic acid,dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid,trimethylacetic acid, trifluoroacetic acid and the like.

By “halogen atom” in the present invention is meant atoms of fluorine,chlorine, bromine and iodine.

By “(C₁-C₆)alkyl” in the present invention is meant a linear orbranched, saturated hydrocarbon chain comprising 1 to 6 carbon atoms. Inparticular it may be a methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl group.

By “(C₁-C₆)alkoxy” in the present invention is meant a (C₁-C₆)alkylgroup as defined above attached to the remainder of the molecule via anoxygen atom. It may in particular be a methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy orn-hexoxy group.

By “aryl” in the present invention is meant an aromatic hydrocarbongroup preferably having 5 to 10 carbon atoms and comprising one or morefused rings, preferably 1 or 2 rings, e.g. a phenyl or naphthyl group.Advantageously it is phenyl.

By “(C₁-C₆)alkyl-aryl” in the present invention is meant a (C₁-C₆)alkylgroup as defined above attached to the remainder of the molecule via anaryl group as defined above. In particular it may be a tolyl group.

By “aryl-(C₁-C₆)alkyl” in the present invention is meant an aryl groupas defined above attached to the remainder of the molecule via a(C₁-C₆)alkyl group as defined above. In particular, it may be a benzylgroup.

By “biaryl” in the present invention is meant an aryl group as definedabove attached to the remainder of the molecule via an aryl group asdefined above. In particular it may be a biphenyl group.

By “heteroaryl” group in the present invention is meant an aryl group asdefined above wherein one or more carbon atoms have been replaced by oneor more heteroatoms, advantageously 1 to 4, preferably 1 or 2. Examplesof heteroaryl groups are pyridine, pyrimidine, pyrazine, pyridazine,furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole,oxazole, isoxazole, triazole, tetrazole, benzofuran, benzothiophene,indole, benzimidazole, indazole, quinoline, isoquinoline, quinazoline orquinoxaline groups.

By “heteroatom” is particularly meant a sulfur, nitrogen or oxygen atom.

Par “carbocycle” in the present invention is meant one or more fusedrings, preferably 1 or 2 saturated, unsaturated or aromatic hydrocarbonfused rings, each ring advantageously having 3 to 8 members, preferably3, 5, 6 or 7 members, more preferably 5 or 6 members. It may inparticular be a cycloalkyl such as a cyclopentyl or cyclohexyl.

By “unsaturated” in the present invention is meant that the ringcomprises one or more double bonds.

By “carbocycle-(C₁-C₆)alkyl” in the present invention is meant acarbocycle group as defined above attached to the remainder of themolecule via a (C₁-C₆)alkyl group as defined above, preferably via a—CH₂— group. In particular, it may be a cyclopentyl-methyl orcyclohexyl-methyl group.

By “heterocycle” in the present invention is meant a carbocycle group asdefined above wherein one or more carbon atoms have been replaced by oneor more heteroatoms, advantageously 1 to 4, preferably 1 or 2. Examplesof heterocycles comprising only 1 ring are the rings: epoxide,aziridine, furan, dihydrofuran, tetrahydrofuran, pyrrole, pyroline,pyrrolidine, thiophene, dihydrothiophene, tetrahydrothiophene, pyrazole,pyrazoline, pyrazolidine, imidazole, imidazoline, imizadolidine,thiazole, dihydrothiazole, tetrahydrothiazole, oxazole, dihydrooxazole,tetrahydrooxazole, triazoles, dihydrotriazoles, tetrahydrotriazoles,pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyrimidine,pyridazine, pyrazine, dihydropyrimidine, dihydropyridazine,dihydropyrazine, tetrahydropyrimidine, tetrahydropyridazine,tetrahydropyrazine, hexahydropyrimidine, hexahydropyridazine,piperazine, pyran, dihydropyran, tetrahydropyran, oxazines,dihydrooxazines, tetrahydrooxazines (e.g. morpholine), azepine,dihydroazepine, tetrahydroazepine, azepane, diazepines,dihydrodiazepines, tetrahydrodiazepines and diazepanes. Examples ofheterocycles comprising 2 fused rings are the previously mentioned1-ring heterocycles fused with 1 phenyl core such as indole, benzofuran,benzopyran including chromene and isochromene, dihydrobenzopyransincluding chromane, quinoline, dihydroquinolines, tetrahydroquinoline,isoquinoline, dihydroisoquinolines and tetrahydroisoquinoline.

By “heterocycle-(C₁-C₆)alkyl” in the present invention is meant aheterocycle group as defined above attached to the remainder of themolecule via a (C₁-C₆)alkyl group as defined above, and preferably via a—CH₂— group.

By “cycloalkyl” in the present invention is meant a saturated,hydrocarbon, monocycle advantageously comprising 3 to 8 carbon atoms, inparticular 5 or 6. In particular, it may be a cyclohexyl.

According to one particular embodiment of the invention:

R₁ to R₅ are each independently a hydrogen atom or a (C₁-C₆)alkyl, aryl,(C₁-C₆)alkyl-aryl or aryl-(C₁-C₆)alkyl group;

R₆ is a hydrogen atom or a (C₁-C₆)alkyl, aryl, (C₁-C₆)alkyl-aryl,aryl-(C₁-C₆)alkyl, C(O)NH₂ or C(S)NH₂ group; and

R₇ is a (C₁-C₆)alkyl, aryl, (C₁-C₆)alkyl-aryl or aryl-(C₁-C₆)alkylgroup.

According to the invention, Y is C═O, C═S, CH₂, CH—OR₁, CHN₃, CHNR₂R₃,C═N—OR₄ or C═N—NR₅R₆, for example C═O, CH—OR₁, CHN₃, CHNR₂R₃, C═N—OR₄ orC═N—NR₅R₆, and advantageously C═O, CH—OR₁, C═N—OR₄, or C═N—NR₅R₆ group,in particular C═O or CH—OR₁ such as C═O or CH—OH, and particularly C═O.

advantageously represents a double bond.

In a first embodiment, Z is a —S(O)R₇ or —S(O)₂R₇ group, and X is aCH—R₈ group when

represents a single bond, or C—R₈ when

represents a double bond, preferably X represents C—R₈.

R₇ is a (C₁-C₆)alkyl, aryl, (C₁-C₆)alkyl-aryl or aryl-(C₁-C₆)alkylgroup, preferably an aryl or (C₁-C₆)alkyl-aryl group.

R₈ advantageously represents a R₁₁ group.

R₁₁ is advantageously a hydrogen atom or a (C₁-C₆)alkyl, carbocycle,heterocycle, biaryl, carbocycle-(C₁-C₆)alkyl or heterocycle-(C₁-C₆)alkylgroup, optionally substituted; in particular a hydrogen atom or a(C₁-C₆)alkyl, carbocycle, heterocycle or biaryl group, optionallysubstituted; preferably a hydrogen atom or a (C₁-C₆)alkyl group such asa CH₃ group; for example a hydrogen atom,

-   the carbocycle advantageously being a cycloalkyl such as a    cyclohexyl or an aryl such as phenyl or naphthyl,-   the heterocycle advantageously being pyridine, pyrimidine,    pyridazine, pyrazine, furan, thiophene, pyrrole, pyrazole,    imidazole, thiazole, oxazole, triazoles, benzofuran, benzothiophene,    indole, 1,3-benzodioxolane, piperidine, morpholine or piperazine;    particularly pyridine, furan, thiophene, pyrrole, benzofuran,    benzothiophene, indole, 1,3-benzodioxolane or piperidine and more    particularly pyridine, furan, thiophene, benzofuran,    1,3-benzodioxolane or piperidine, and-   the biaryl advantageously being biphenyl.

When the (C₁-C₆)alkyl, carbocycle, heterocycle, biaryl,carbocycle-(C₁-C₆)alkyl or heterocycle-(C₁-C₆)alkyl group of R₁₁ issubstituted, it is advantageously substituted with a halogen atom; anoxo group (═O); CN; CO₂H; CO₂—(C₁-C₆)alkyl; OH; NR₁₈R₁₉, an aryloptionally substituted with one or more substituents selected from amonga halogen atom, (C₁-C₆)alkyl, OH or (C₁-C₆)alkoxy; a heterocycle; or a(C₁-C₆)alkyl or (C₁-C₆)alkoxy group optionally substituted with one ormore substituents selected from among a halogen atom, a (C₁-C₆)alkoxygroup, a heterocycle or NR₂₀R₂₁,

-   the groups R₁₈ to R₂₁ each independently representing a hydrogen    atom or a (C₁-C₆)alkyl or aryl group, and-   the heterocycles optionally being substituted with an oxo,    (C₁-C₆)alkyl or CO₂—(C₁-C₆)alkyl group.

In a second embodiment, Z is a hydrogen atom or a R₉ group, and X is aCH—R₁₀ group when

represents a single bond, or C—R₁₀ when

represents a double bond, preferably X represents a C—R₁₀ group.

Z is preferably a hydrogen atom.

When Z represents a —R₉ group, R₉ preferably represents a R₁₄ group,

R₁₄ then preferably representing a hydrogen atom or a (C₁-C₆)alkyl,carbocycle, heterocycle, biaryl, carbocycle-(C₁-C₆)alkyl orheterocycle-(C₁-C₆)alkyl group, optionally substituted; in particular a(C₁-C₆)alkyl, carbocycle, heterocycle or biaryl group, optionallysubstituted; preferably a (C₁-C₆)alkyl group such as a CH₃ group,

-   the carbocycle advantageously being a cycloalkyl such as cyclohexyl    or an aryl such as phenyl or naphthyl,-   the heterocycle advantageously being pyridine, pyrimidine,    pyridazine, pyrazine, furan, thiophene, pyrrole, pyrazole,    imidazole, thiazole, oxazole, triazoles, benzofuran, benzothiophene,    indole, 1,3-benzodioxolane, piperidine, morpholine or piperazine;    particularly pyridine, furan, thiophene, pyrrole, benzofuran,    benzothiophene, indole, 1,3-benzodioxolane or piperidine; more    particularly pyridine, furan, thiophene, benzofuran,    1,3-benzodioxolane or piperidine, and-   the biaryl advantageously being the biphenyl.

When the (C₁-C₆)alkyl, carbocycle, heterocycle, biaryl,carbocycle(C₁-C₆)alkyl or heterocycle-(C₁-C₆)alkyl group of R₁₁ issubstituted, it is advantageously substituted with a halogen atom; anoxo group (═O); CN; CO₂H; CO₂—(C₁-C₆)alkyl; OH; NR₂₂R₂₃, an aryloptionally substituted with one or more substituents selected from amonga halogen atom, (C₁-C₆)alkyl, OH or (C₁-C₆)alkoxy; a heterocycle; or a(C₁-C₆)alkyl or (C₁-C₆)alkoxy group optionally substituted with one ormore substituents selected from among a halogen atom, a (C₁-C₆)alkoxygroup, a heterocycle or NR₂₄R₂₅,

-   the groups R₂₂ to R₂₅ each independently representing a hydrogen    atom or a (C₁-C₆)alkyl or aryl group, and-   the heterocycles optionally being substituted with an oxo,    (C₁-C₆)alkyl or CO₂—(C₁-C₆)alkyl group.

R₁₀ preferably represents a —S(O)₂R₁₅ group.

R₁₅ represents optionally substituted (C₁-C₆)alkyl, optionallysubstituted aryl, (C₁-C₆)alkyl-aryl, aryl-(C₁-C₆)alkyl, carbocycle,optionally substituted heterocycle, biaryl, carbocycle-(C₁-C₆)alkyl orheterocycle-(C₁-C₆)alkyl.

When the (C₁-C₆)alkyl, aryl or heterocycle group of R₅ is substituted,it is advantageously substituted with one or more substituents selectedfrom among a halogen atom; an oxo group (═O) [except for the arylgroup]; CO₂R₂₆; OR₂₇; NR₂₈R₂₉; (C₁-C₆)alkyl group; and an aryloptionally substituted with one or more substituents selected from amonga halogen atom, (C₁-C₆)alkyl, OH or (C₁-C₆)alkoxy,

-   particularly selected from among a halogen atom; oxo group (═O)    [except for the aryl group]; CO₂R₂₆; OR₂₇; NR₂₈R₂₉; (C₁-C₆)alkyl;-   selected in particular from among CO₂R₂₆, OR₂₇ and NR₂₈R₂; more    particularly from among OR₂₇ and NR₂₈R₂₉,-   the groups R₂₆ to R₂₉ each independently representing a hydrogen    atom or (C₁-C₆)alkyl or aryl group.

R₁₅ is preferably a (C₁-C₆)alkyl group optionally substituted with oneor more groups (in particular one group) selected from among CO₂R₂₆,OR₂₇ and NR₂₈R₂₉, more particularly from among OR₂₇ and NR₂₈R₂₉; aryl;(C₁-C₆)alkyl-aryl; or aryl-(C₁-C₆)alkyl.

In particular, the compounds of the invention can be selected from amongthe following examples:

Compound N° Structures 95

96

97

98

145

146

147

148

A further subject of the invention is a formula (I) compound of theinvention such as defined above, for use as a drug, notably intended forthe treatment of cancerous and pre-cancerous hyperproliferativepathologies.

The present invention also concerns the use of a formula (I) compoundsuch as defined above in the manufacture of a drug, notably intended forthe treatment of cancerous and pre-cancerous hyperproliferativepathologies.

The present invention also concerns a method for treating cancerous andpre-cancerous hyperproliferative pathologies, comprising theadministration of an efficient dose of a formula (I) compound as definedabove to a person in need thereof.

By “cancerous or pre-cancerous hyperproliferative pathologies” in thepresent invention is meant all types of cancerous or precanceroushyperproliferative pathologies, in particular lung cancer, breastcancer, brain cancer and skin cancers.

By “skin cancer” in the present invention is meant actinic keratosis,solar keratosis, keratinocyte intraepithelial neoplasia, cutaneouspapilloma, in situ epidermoid carcinoma, epidermoid carcinoma,pre-cancerous skin lesions, basal cell carcinoma including surface andnodular forms, Bowen's disease, Dubreuilh's melanoma, condylomas, Merkelcell tumour, Paget's disease, or cutaneous-mucosal lesions caused byhuman papilloma virus.

The present invention also concerns a pharmaceutical compositioncomprising at least one formula (I) compound as defined above, and atleast one pharmaceutically acceptable excipient.

The pharmaceutical compositions of the invention can be formulated inparticular for oral administration, for administration via topical routeor via injection, the said compositions being more particularly intendedfor mammals including human.

The active ingredient can be administered in unit administration forms,in a mixture with conventional pharmaceutical carriers, to animalsincluding human beings. The compounds of the invention as activeingredients can be used at doses of between 0.01 mg and 1000 mg per day,given in a single dose once daily or administered in several dosesthroughout the day, for example twice a day in equal doses. The doseadministered per day is advantageously between 5 mg and 500 mg, moreadvantageously between 10 mg and 200 mg. It may be necessary to usedoses outside these ranges as can be determined by persons skilled inthe art.

The pharmaceutical compositions of the invention may also comprise atleast one other active ingredient such as an anti-cancer agent.

The present invention further concerns a pharmaceutical composition suchas defined above for use as a drug, notably intended for the treatmentof cancerous and pre-cancerous hyperproliferative pathologies

The present invention is illustrated by the following non-limitingexamples.

EXAMPLE 1 Synthesis of the Compounds of the Invention AbbreviationsUsed:

-   DMF Dimethylformamide-   DMSO Dimethylsulfoxide-   equiv./eq. Eq.uivalent-   PE Petroleum ether-   ES Electrospray ionization-   HPLC High Performance Liquid Chromatography-   LCMS Liquid chromatography coupled with mass spectrometry-   NMR Nuclear Magnetic Resonance-   rt Room temperature-   THF Tetrahydrofuran-   The compounds of the invention were often obtained in the form of    two diastereoisomers which were able to be separated. However, among    the two NMR spectra obtained it was not determined to which spectrum    each of these two diastereoisomers corresponded.

1.1. Synthesis of a Sulfoxide at 3′

-   A 2 L round-bottomed flask was charged with 3 g of Pd/C in a    solution of griseofulvin (20 g, 5.7 mmol) in 1.2 L of AcOEt. The    mixture was left under agitation in a hydrogen atmosphere (1 bar) at    ambient temperature for 60 h, then filtered. The filtrate was    concentrated under reduced pressure. A white solid was obtained    (20 g) and used as crude product at the following step.

(2S,6′R)-7-chloro-4,6-dimethoxy-6′-methyl-3H-spiro[benzofuran-2,1′-cyclohexan]-2′-ene-3,4′-dione

-   In a 2 L round-bottomed flask 600 mL of 2N sulfuric acid was added    dropwise to a solution of the product previously obtained (60 g,    169.1 mmol) in 600 mL of ethanol. The resulting solution was heated    under reflux for 16 h, then cooled to ambient temperature. The    reaction medium was extracted with 2×400 mL of dichloromethane. The    organic phases were combined, dried over anhydrous sodium sulfate    and concentrated under reduced pressure. A pale yellow solid (54 g)    was obtained with a yield of 99%.-   ¹H NMR (CDCl₃, 400 MHz, δ, ppm): 6.57 (1H, d), 6.19 (1H, d), 6.15    (1H, s), 4.04 (3H, s), 4.00 (3H, s), 3.12 (1H, dd), 2.94-2.81 (1H,    m), 2.42 (1H, dd), 0.97 (3H, d) LCMS (ES, m/z): 322.90 [M+H]⁺

(2S,3′R)-7-chloro-4,6-dimethoxy-3′-methyl-3H-7′-oxaspiro[benzofuran-2,2′-bicyclo[4.1.0]heptane]-3,5′-dione

-   In a 100 mL round-bottomed flask a 2N solution of NaOH was added    dropwise to a solution of 0.5 g (1.55 mmol, 1 equiv.) of the product    previously obtained in 20 mL of ethanol under agitation at 0° C.    H₂O₂ (1 mL) was added dropwise to the agitated solution at 0° C. The    reaction mixture was left under agitation 1 h at 0° C. then diluted    in 100 mL of water. The solution was extracted with 3×100 mL of    AcOEt. The organic phases were combined, dried over anhydrous sodium    sulfate and filtered. The filtrate was concentrated under reduced    pressure. A pale yellow solid (m=0.5 g) was obtained with a yield of    95%.-   ¹H NMR (DMSO-d6, 400 MHz, δ, ppm): 6.52 (1H, s), 4.05 (3H, s),    4.05-4.00 (1H, m), 3.94 (3H, s), 3.58-3.56 (1H, m), 2.80-2.68 (1H,    m), 2.65-2.55 (1H, m), 2.31-2.21 (1H, m), 0.63 (3H, d)-   LCMS (ES, m/z): 338.85 [M+H]⁺-   In a 100 mL round-bottomed flask 4 mL of 0.1 N NaOH was added to a    solution of thiophenol (176 mg, 1.6 mmol, 1.2 eq.) in 20 mL of    water. The mixture was agitated 10 min at 30° C. The previously    obtained product (0.45 g, 1.3 mmol, 1.0 eq.) was added and the    mixture left under agitation 1 h at 30° C., then 16 h at 70° C. The    reaction mixture was cooled to ambient temperature then extracted    with 3×30 mL AcOEt. The organic phases were combined, dried over    anhydrous sodium sulfate, filtered and concentrated under reduced    pressure. The residue was purified by chromatography on silica gel    (AcOEt/EP 1:2). A pale yellow solid (360 mg) was obtained with a    yield of 63%.

1′S,6′R)-7-chloro-4,6-dimethoxy-6′-methyl-3′-(phenylsulfinyl)-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione

-   95 In a 100 mL round-bottomed flask, to a solution of the product    previously obtained (0.35 g, 0.8 mmol, 1.0 eq.) in 20 mL methanol    was added 261 mg (1.2 mmol, 1.5 eq.) of sodium periodate dissolved    in 10 mL of water. The solution was left under agitation at 50° C.    for 16 h. The reaction mixture was cooled to ambient temperature and    extracted with 3×50 mL of dichloromethane. The organic phases were    combined, dried over anhydrous sodium sulfate, filtered and    concentrated under reduced pressure. The residue was purified by    chromatography on silica gel (EtOAc/EP 1:2). A white solid (0.2 g)    was obtained with a yield of 55 %.-   ¹H NMR (300 MHz, CD₃OD, δ, ppm): 7.78-7.84 (1H, m), 7.70-7.73 (1H,    dd, J=6 Hz), 7.51-7.58 (3H, m), 7.28-7.30 (1H, d, J=5.4 Hz), 6.48    (1H, s), 4.85 (3H, s), 4.09 (3H, s), 2.73-3.07 (2H, m), 2.41-2.54    (1H, m), 0.86-0.90 (3H, t, J=6.6 Hz); LCMS (ES, m/z): 447 [M+H]⁺-   The following sulfoxides were prepared following similar procedure.

(1′S,6′R)-3′-(benzylsulfonyl)-7-chloro-4,6-dimethoxy-6′-methyl-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione

-   96 White solid 79% yield; ¹H (CDCl₃, 400 MHz, δ, ppm): 0.93 (d, 3H,    J=6.7 Hz), 2.63 (dd, 1H, J=17.6, 5.3 Hz), 2.80 (m, 1H), 3.21 (dd,    1H, J=17.6, 13.7 Hz), 3.98 (s, 3H), 4.03 (s, 3H), 4.56 (d, 1H,    J=13.7 Hz), 4.63 (d, 1H, J=13.7 Hz), 6.14 (s, 1H), 7.27-7.34 (m,    5H); LCMS (ES, m/z): 477.1 [M+H]⁻

(1′S,6′R)-3′-(benzylsulfinyl)-7-chloro-4,6-dimethoxy-6′-methyl-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione

-   97 White solid 30% yield; ¹H (CDCl₃, 400 MHz, δ, ppm): 0.97 (d, 3H,    J=6.7 Hz), 2.60 (dd, 1H, J=17.3, 5.0 Hz), 2.88-2.96 (m, 1H), 3.27    (dd, 1H, J=17.4, 13.8 Hz), 3.90 (d, 1H, J=13.0 Hz), 4.01 (s, 3H),    4.03 (s, 3H), 4.35 (d, 1H, J=13.0 Hz), 6.14 (s, 1H), 6.87 (s, 1H),    7.20 (d, 2H, J=7.7 Hz), 7.26-7.34 (m, 3H); LCMS (ES, m/z): 461.1    [M+H]⁺

(1′S,6′R)-7-chloro-4,6-dimethoxy-6′-methyl-3′-(phenylsulfonyl)-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione

-   98 White solid 46% yield; ¹H (CDCl₃, 400 MHz, δ, ppm): 0.92 (d, 3H,    J=6.7 Hz), 2.46 (dd, 1H, J=17.2, 4.9 Hz), 2.86-2.94 (m, 1H), 3.13    (dd, 1H, J=17.2, 14.0 Hz), 4.00 (s, 3H), 4.06 (s, 3H), 6.18 (s, 1H),    7.52 (t, 2H, J=7.4 Hz), 7.62 (t, 1H, J=7.4 Hz), 7.78 (s, 1H), 8.01    (d, 2H, J=7.4 Hz); LCMS (ES, m/z): 463.0 [M+H]⁻

1.2. Forming of Sulfones at 2′ Method A:

-   Example: R=Bn

Synthesis of the Sulfide:

-   In a 100 mL round-bottomed flask, thiol (RSH) (5.6 mmol, 2 eq.) was    added to a 1 g solution of (1′R,6′R)-2′,7-dichloro-4,    6-dimethoxy-6′-methyl-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione    (1 g, 2.8 mmol, 1 eq.) and 1.05 mL of    1,8-diazabicyclo[5.4.0]undec-7-ene (7.0 mmol, 2.5 eq.) dissolved in    10 mL of 1,4-dioxane. The mixture was brought to 100° C. for 16 h.    The reaction mixture was then cooled to ambient temperature and    diluted in water and dichloromethane. The organic phase was washed    with saturated NaHCO₃ solution, dried over MgSO₄, filtered and    concentrated under reduced pressure. The residue was purified by    chromatography on silica gel (eluting with    dichloromethane/methanol).

Synthesis of the Sulfone:

-   In a 250 ml round-bottomed flask, 4.6 g of oxone monopersulfate    (13.0 mmol) dissolved in 46 ml of water was added to a solution of    the sulfide (768 mg, 1.7 mmol) in 15 mL of methanol (15 mL) and 15    mL of THF. The reaction mixture was left under agitation at ambient    temperature for 16 h. The solids were filtered and rinsed with    methanol. The filtrate was concentrated under reduced pressure then    diluted in AcOEt and water. The aqueous phase was extracted with    AcOEt. The organic phases were combined, dried over MgSO₄, filtered    and concentrated under reduced pressure. The residue was purified by    chromatography on silica gel (CH₂Cl₂/AcOEt 98:2). A beige solid    (0.26 g) was obtained with a yield of 32%.

Method B:

-   Example R=Ph (147)-   In a 50 mL round-bottomed flask, 46 mg (0.28 mmol, 1 eq.) of sodium    benzenesulfinate was added to a solution of 100 mg of    (1′R,6′R)-2′,7-dichloro-4,6-dimethoxy-6′-methyl-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione    (0.28 mmol, 1 eq.) in 1 mL of DMF. The mixture was left under    agitation at ambient temperature for 16 h. Water was added to the    reaction medium and the precipitate obtained was filtered, rinsed    with water and dried under reduced pressure. A white solid was    obtained with a yield of 86%.

(1′R,6′R)-2′-(benzylsulfonyl)-7-chloro-4,6-dimethoxy-6′-methyl-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione

-   145 ¹H NMR (CDCl₃, 400 MHz, δ, ppm): 0.96 (d, 3H, J=6.8 Hz), 2.39    (dd, 1H, J=17.6, 4.8 Hz), 2.74 (m, 1H), 3.07 (dd, 1H, J=17.6, 14.0    Hz), 3.99 (s, 3H), 4.06 (s, 3H), 4.49 (d, 1H, J=13.6 Hz), 4.69 (d,    1H, J=13.6 Hz), 6.19 (s, 1H), 6.52 (s, 1H), 7.37 (m, 3H), 7.49 (m,    2H); LCMS (ES, m/z): 477.07 [M+H]⁺

(1′R,6′R)-7-chloro-2′-(2-(dimethylamino)ethylsulfonyl)-4,6-dimethoxy-6′-methyl-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione

-   146 pale yellow solid, yield 11%; ¹H NMR (CDCl₃, 400 MHz, δ, ppm):    0.95 (d, 3H, J=6.8 Hz), 2.27 (s, 6H), 2.50 (dd, 1H, J=17.6, 4.8 Hz),    2.66 (dt, 1H, J=13.2, 5.2 Hz), 2.87 (m, 2H), 3.18 (m, 2H), 3.77    (ddd, 1H, J=14.4, 8.8, 6.0 Hz), 3.98 (s, 3H), 4.03 (s, 3H), 6.16 (s,    1H), 6.88 (s, 1H); LCMS (ES, m/z): 458.096 [M+H]⁺

(1′R,6′R)-7-chloro-4,6-dimethoxy-6′-methyl-2′-(phenylsulfonyl)-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione

-   147 pale yellow solid, yield 13%; ¹H NMR (CDCl₃, 400 MHz, δ, ppm):    0.83 (d, 1H, J=6.8 Hz), 2.44 (dd, 1H, J=17.2, 4.8 Hz), 2.77 (m, 1H),    3.11 (dd, 1H, J=17.2, 14.0 Hz), 4.00 (s, 3H), 4.05 (s, 3H), 6.18 (s,    1H), 7.11 (s, 1H), 7.54 (t, 2H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz),    7.83 (d, 2H, J=7.2 Hz); LCMS (ES, m/z): 463.054 [M+H]⁺

(1′R,6′R)-7-chloro-4,6-dimethoxy-6′-methyl-2′-(methylsulfonyl)-3H-spiro[benzofuran-2,1′-cyclohex[2]ene]-3,4′-dione

-   148 pale yellow solid, yield 12%; ¹H NMR (CDCl₃, 400 MHz, δ, ppm):    0.97 (d, 3H, J=6.8 Hz), 2.52 (dd, 1H, J=17.2, 4.4 Hz), 2.94 (m, 1H),    3.17 (dd, 1H, J=17.2, 14.0 Hz), 3.22 (s, 3H), 3.98 (s, 3H), 4.03 (s,    3H), 6.16 (s, 1H), 6.98 (s, 1H); LCMS (ES, m/z): 401.038 [M+H]⁺

EXAMPLE 2 Cytotoxic Activity of the Compounds of the Invention Cultureof Lines and Measurement of Cell Viability:

-   The lines N1E115 (ATCC, CRL2263), MDA-MB-231 (ATCC, HTB26) and HSC-1    (Health Science Research Resources Bank, JCRB1015) were cultured in    DMEM medium (Dulbecco's modified Eagle medium) supplemented with 2    mM of L-Glutamine (Sigma, G7513) and 10% foetal calf serum (Hyclone,    SH30109.03) or 20% for the HSC-1 cells. The HCC-1937 (ATCC, CRL2336)    and A549 (ATCC, CCL185) lines were cultured in RPMI medium (Roswell    Park Memorial Institute medium) supplemented with 10% foetal calf    serum and 2 mM of L-Glutamine. Finally, the SCC114 line (DSMZ,    ACC662) was cultured in MEM medium (Minimum Essential Medium Eagle)    supplemented with 10% foetal calf serum and 2 mM of L-Glutamine.    Initially, in 96-well plates (Perkin Elmer, 6005668), the cells were    seeded in their respective culture media with 750 cells per well for    N1E115; 1000 cells per well for SCC114 and A549; 2000 cells per well    for HCC-1937 and HSC-1; 2500 cells per well for MDA-MB-231. Cascade    dilution of each compound was performed in dimethylsulfoxide (DMSO)    (Sigma, D8418) using 10 mM stock solutions in 100% DMSO.-   Each of the dilutions was added to the cells 24 hours after seeding.    Under these conditions the final solvent concentration was 0.1%    DMSO. Reading of cell proliferation was conducted 72 hours after    addition of products with the ATPLite kit (Perkin Elmer, 6016947)    and following the manufacturer's directions except in the case of    the HCC-1937 line for which this reading was carried out 48 hours    after treatment. Analysis of proliferation results was performed by    comparing with conditions in which solely the vehicle was added to    the cells. The dose-response curves obtained were analysed using    Prism 4.03 software (GraphPad Software Inc.) to determine the    concentration of each compound allowing 50% inhibition of cell    proliferation (IC₅₀).-   As examples, the cytotoxic properties of some compounds of the    invention evaluated on the lines A549 (lung cancer cell line),    MDA-MB-231 (mammary adenocarcinoma cell line), N1E115 (mouse brain    neuroblastoma cell line), HCC-1937 1 (primary ductal breast    carcinoma cell line), HSC-1 (cutaneous squamous carcinoma cell line)    and SCC114 (oral squamous carcinoma cell line) are reported in Table    1, as compared with griseofulvin used as control product. The    concentration values are expressed in micromolar units (μM).

TABLE 1 IC₅₀ (μM) Compound N1E-115 MDA-MB-231 SCC114 HCC1937 HSC-1 A549Griseofulvin >10 >10 6.4 >10 >10 >10 GF-15* 1.1 1 0.98 >10 4.3 2.9 95 10.54 0.25 0.43 0.32 0.25 96 0.92 97 0.021 0.14 98 0.41 0.7 0.76 145 3 20.385 1.4 1.4 1.5 146 5.9 147 1.6 *compound 15 of J. Med. Chem. 2009,3342-3347

-   The activity of the compounds of the invention on the HCC1997 line    was compared with that of known cytotoxics (Epotilone B and    Vinflunine). The compounds of the invention exhibit particularly    remarkable activity on this particularly resistant breast cancer    cell line.-   Additionally, comparative examples were performed between the    compounds of the invention and compounds substituted at 2′ with an    SR₇ group. It is shown herein that substitution by a —S(O)R₇ or    —SO₂R₇ group significantly improves the cytotoxic activity of the    compounds compared with substitution with a —SR₇ group (compound 145    versus A and compound 146 versus B).-   All these results are given in following Table 2.

TABLE 2 IC₅₀ (μM) Compound Structure HCC1937  95

0.43  98

0.7  96

0.92 147

1.6 145

1.4 A

>10 B

>10 146

5.9 Epotilone B

>10 Vinflunine

>10

1. A compound of following formula (I):

or a pharmaceutically acceptable salt thereof, where:

represents a single or double bond; Y is C═O, C═S, CH₂, CH—OR₁, CHN₃,CHNR₂R₃, C═N—OR₄, C═N—NR₅R₆, Z is a hydrogen atom or a R₉ group, and Xis a CH—R₁₀ group when

represents a single bond or a C—R₁₀ group when

represents a double bond, with: R₁ to R₅ each independently representinga hydrogen atom or a (C₁-C₆)alkyl, aryl, (C₁-C₆)alkyl-aryl,aryl-(C₁-C₆)alkyl or 5- or 6-membered heterocycle group; R₆ representinga hydrogen atom or a (C₁-C₆)alkyl, aryl, (C₁-C₆)alkyl-aryl,aryl-(C₁-C₆)alkyl, C(O)NH₂, C(S)NH₂ or 5- or 6-membered heterocyclegroup; R₉ representing —R₁₄, —NHR₁₄, —CH₂—NHR₁₄, —CH₂—NH—C(O)—R₁₄,—NH—CH₂—R₁₄, —NH—NH—R₁₄, —NH—C(O)—R₁₄, —NH—C(O)—CH₂—R₁₄,—NH—CH₂—C(O)—R₁₄, —NH—CH₂—C(O)—O—R₁₄, —NH—CH₂—C(O)—NH—R₁₄, —NH—SO₂—R₁₄,—S(O)—R₁₄, —SO₂—R₁₄, —S(O)—CH₂—R₁₄, —SO₂—CH₂—R₁₄ or —NR₁₆R₁₇; R₁₀representing a —S(O)R₁₅ or —S(O)₂R₁₅ group; R₁₄ representing a(C₁-C₆)alkyl, carbocycle, heterocycle, biaryl, carbocycle-(C₁-C₆)alkylor heterocycle-(C₁-C₆)alkyl group, optionally substituted; R₁₅representing optionally substituted (C₁-C₆)alkyl, optionally substitutedaryl, (C₁-C₆)alkyl-aryl, aryl-(C₁-C₆)alkyl, carbocycle, optionallysubstituted heterocycle, biaryl, carbocycle-(C₁-C₆)alkyl orheterocycle-(C₁-C₆)alkyl, and R₁₆ and R₁₇ together forming, with theircarrier nitrogen atom, a heterocycle optionally substituted with —R₁₄,—OR₁₄ or —NHR₁₄.
 2. The compound according to claim 1, wherein: R₁ to R₅are each independently a hydrogen atom or a (C₁-C₆)alkyl, aryl,(C₁-C₆)alkyl-aryl or aryl-(C₁-C₆)alkyl group; and R₆ is a hydrogen atomor a (C₁-C₆)alkyl, aryl, (C₁-C₆)alkyl-aryl, aryl-(C₁-C₆)alkyl, C(O)NH₂or C(S)NH₂ group.
 3. The compound according to claim 1, wherein Y isC═O, C═S, CH—OR₁, CHN₃, CHNR₂R₃, C═N—OR₄ or C═N—NR₅R₆.
 4. The compoundaccording to claim 1, wherein Y is C═O, CH—OR₁, CHN₃, CHNR₂R₃, C═N—OR₄or C═N—NR₅R₆.
 5. The compound according to claim 1, wherein Y is C═O,CH—OR₁, C═N—OR₄ or C═N—NR₅R₆.
 6. The compound according to claim 1,wherein Y is a C═O or CH—OR₁ group.
 7. The compound according to claim1, wherein Y is C═O.
 8. The compound according to claim 1, wherein Z isa hydrogen atom.
 9. The compound according to claim 1, wherein R₁₀preferably represents a —S(O)₂R₁₅ group.
 10. The compound according toclaim 1, wherein R₁₅ is a (C₁-C₆)alkyl group optionally substituted withone or more groups selected from among CO₂R₂₆, OR₂₇ and NR₂₈R₂₉; an arylgroup; a (C₁-C₆)alkyl-aryl group; or an aryl-(C₁-C₆)alkyl group.
 11. Thecompound according to claim 1, selected from among: Compound N°Structures 145

146

147

148


12. A pharmaceutical composition comprising at least one compoundaccording to claim 1 and at least one pharmaceutically acceptableexcipient.
 13. A method for treating cancerous and pre-canceroushyperproliferative pathologies comprising the administration of anefficient dose of a compound according to claim 1 to a person in needthereof.
 14. The method according to claim 13, wherein the cancerous orpre-cancerous hyperproliferative pathology is selected from among lungcancer, breast cancer, brain cancer and skin cancers.
 15. The methodaccording to claim 14, wherein the skin cancer is selected from amongactinic keratosis, solar keratosis, keratinocyte intraepithelialneoplasia, cutaneous papilloma, in situ squamous cell carcinoma,squamous cell carcinoma, pre-cancerous skin lesions, basal cellcarcinoma, Bowen's disease, Dubreuilh's melanoma, condylomas, Merkel'scell tumour, Paget's disease, and cutaneous-mucosal lesions caused byhuman papilloma virus.
 16. The method according to claim 15, wherein thebasal cell carcinoma is in surface and nodular forms.